Human ADAM-10 inhibitors

ABSTRACT

The present invention provides compounds useful for inhibiting the ADAM-10 protein, with selectivity versus MMP-1. Such compounds are useful in the in vitro study of the role of ADAM-10 (and its inhibition) in biological processes. The present invention also comprises pharmaceutical compositions comprising one or more ADAM-10 inhibitors according to the invention in combination with a pharmaceutically acceptable carrier. Such compositions are useful for the treatment of cancer, arthritis, and diseases related to angiogenesis. Correspondingly, the invention also comprises methods of treating forms of cancer, arthritis, and diseases related to angiogenesis in which ADAM-10 plays a critical role.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage entry of PCT/US03/18262, whichclaims the benefit under 35 U.S.C. § 119(e) to application Ser. No.60/388,326, filed Jun. 12, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is in the field of agents that inhibit humanADAM-10 (also known as human Kuzbanian) and their use in the treatmentof cancer, arthritis, and diseases related to angiogenesis, such asrenal diseases, heart diseases such as heart failure, atherosclerosis,and stroke, inflammation, ulcer, infertility, scleroderma,endometriosis, mesothelioma, and diabetes.

2. Summary of the Related Art

Cell-cell interactions play an important role in regulating cell fatedecisions and pattern formation during the development of multicellularorganisms. One of the evolutionarily conserved pathways that plays acentral role in local cell interactions is mediated by the transmembranereceptors encoded by the Notch (N) gene of Drosophila, the lin-12 andglp-1 genes of C. elegans, and their vertebrate homologs (reviewed inArtavanis-Tsakonas, S., et al. (1995) Notch Signaling. Science 268,225-232), collectively hereinafter referred to as NOTCH receptors.Several lines of evidence suggest that the proteolytic processing ofNOTCH receptors is important for their function. For example, inaddition to the full-length proteins, antibodies against theintracellular domains of NOTCH receptors have detected C-terminalfragments of 100-120 kd; see, e.g., Fehon, R. G., et al. (1990). Cell61, 523-534; Crittenden, S. L., et al. (1994). Development 120,2901-2911; Aster, J., et al. (1994) Cold Spring Harbor Symp. Quant.Biol. 59, 125-136; Zagouras, P., et al. (1995). Proc. Natl. Acad. Sci.U.S.A. 92, 6414-6418; and Kopan, R., et al. (1996). Proc. Natl. Acad.Sci. U.S.A. 93, 1683-1688. However, the mechanism(s) of NOTCH activationhave been hitherto largely unknown.

During neurogenesis, a single neural precursor is singled out from agroup of equivalent cells through a lateral inhibition process in whichthe emerging neural precursor cell prevents its neighbors from taking onthe same fate (reviewed in Simpson, P. (1990). Development 109,509-519). Genetic studies in Drosophila have implicated a group of“neurogenic genes” including N in lateral inhibition. Loss-of-functionmutations in any of the neurogenic genes result in hypertrophy of neuralcells at the expense of epidermis (reviewed in Campos-Ortega, J. A.(1993) In: The Development of Drosophila melanogaster M. Bate and A.Martinez-Arias, eds. pp. 1091-1129. Cold Spring Harbor Press.).

Rooke, J., Pan, D. J., Xu, T. and Rubin, G. M. (1996). Science 273,1227-1231, discloses neurogenic gene family, kuzbanian (kuz). Members ofthe KUZ family of proteins are shown to belong to the recently definedADAM family of transmembrane proteins, members of which contain both adisintegrin and metalloprotease domain (reviewed in Wolfsberg, T. G., etal. (1995). J. Cell Biol. 131, 275-278, see also Blobel, C. P., et al.(1992). Nature 356, 248-252, 1992; Yagami-Hiromasa, T., et al. (1995).Nature 377, 652-656; Black, R. A., et al. (1997). Nature 385, 729-733,1997; and Moss, M. L., et al. (1997). Nature 385, 733-736; see also U.S.Pat. Nos. 5,922,546 and 5,935,792).

Genes of the ADAM family encode transmembrane proteins containing bothmetalloprotease and disintegrin domains (reviewed in Black and White,1998 Curr. Opin. Cell Biol. 10, 654-659; Wolfsberg and White, 1996 Dev.Biol. 180, 389-401), and are involved in diverse biological processes inmammals such as fertilization (Cho et al., 1998 Science 281, 1857-1859),myoblast fusion (Yagami-Hiromasa et al., 1995 Nature 377, 652-656) andectodomain shedding (Moss et al., 1997 Nature 385, 733-736; Black etal., 1997 Nature 385, 729-733; Peschon et al., 1998 Science 282,1281-1284). The Drosophila kuzbanian (kuz) gene represents the firstADAM family member identified in invertebrates (Rooke et al., 1996Science 273, 1227-1231). Previous genetic studies showed that kuz isrequired for lateral inhibition and axonal outgrowth during Drosophilaneural development (Rooke et al., 1996; Fambrough et al., 1996 PNAS.USA93, 13233-13238.; Pan and Rubin, 1997 Cell 90, 271-280; Sotillos et al.,1997 Development 124, 4769-4779). Specifically, during the lateralinhibition process, kuz acts upstream of Notch (Pan and Rubin, 1997;Sotillos et al., 1997), which encodes the transmembrane receptor for thelateral inhibition signal encoded by the Delta gene. More recently, ahomolog of kuz was identified in C. elegans (SUP-17) that modulates theactivity of a C. elegans homolog of Notch in a similar manner (Wen etal., 1997 Development 124, 4759-4767).

Vertebrate homologs of kuz have been isolated in Xenopus, bovine, mouse,rat and human. The bovine homolog of KUZ (also called MADM or ADAM 10)was initially isolated serendipitously based on its in vitro proteolyticactivity on myelin basic protein, a cytoplasmic protein that is unlikelythe physiological substrate for the bovine KUZ protease (Howard et al.,1996 Biochem. J. 317, 45-50). Expression of a dominant negative form ofthe murine kuz homolog (mkuz) in Xenopus leads to the generation ofextra neurons, suggesting an evolutionarily conserved role for mkuz inregulating Notch signaling in vertebrate neurogenesis (Pan and Rubin,1997). U.S. patent application. Ser. No. 09/697,854, to Pan et al.,filed Oct. 27, 2000, discloses that mkuz mutant mice die aroundembryonic day (E) 9.5, with severe defects in the nervous system, theparaxial mesoderm and the yolk sac vasculature. In the nervous system,mkuz mutant embryos show ectopic neuronal differentiation. In theparaxial mesoderm, mkuz mutant embryos show delayed and uncoordinatedsegmentation of the somites. These phenotypes are similar to those ofmice lacking Notch-1 or components of the Notch pathway such as RBP-Jk(Conlon et al, 1995, Development 121, 1533-1545; Oka et al., 1995),indicating a conserved role for mkuz in modulating Notch signaling inmouse development. Furthermore, no visible defect was detected in Notchprocessing in the kuz knockout animals. In addition to the neurogenesisand somitogenesis defect, mkuz mutant mice also show severe defects inthe yolk sac vasculature, with an enlarged and disordered capillaryplexus and the absence of large vitelline vessels. Since such phenotypehas not been observed in mice lacking Notch-1 or RBP-Jk (Swiatek et al.,1994 Genes Dev 15, 707-719; Conlon et al, 1995; Oka et al., 1995Development 121, 3291-3301), Pan et al. determined that this phenotypereveals a novel function of mkuz that is distinct from its role inmodulating Notch signaling, specifically, that kuz plays an essentialrole for an ADAM family disintegrin metalloprotease in mammalianangiogenesis.

In view of the important role of KUZ (ADAM-10) in biological processesand disease states, inhibitors of this protein are desirable,particularly small molecule inhibitors.

Studies have suggested that selective inhibition of matrixmetalloproteases is important. A number of small molecule MMPI's haveprogressed into the clinic for cancer and rheumatoid arthritis, forexample. Inhibition of MMP-1 has been implicated as the cause of sideeffects such as joint pain and tendonitis when unselective TACEinhibitors were employed (see Barlaam, B. et. Al. J. Med. Chem. 1999,42, 4890). As well, clinical trials of broad spectrum inhibitors, suchas “Marimastat,” have been hampered due to musculoskeletal syndrome(MSS) which manifests as musculoskeletal pain after a few weekstreatment. Inhibition of MMP-1 has been suggested as having a role inthe appearance of MSS. Recent efforts in the field have been directedtoward design of “MMP-1 sparing” inhibitors; for example, BA-129566emerged as a selective inhibitor which reportedly showed no signs of MSSin phase 2 clinical trials (see Natchus, M. G. et. Al. J. Med. Chem.2000, 43, 4948).

Thus, what is needed are selective matrix metalloprotease inhibitors. Ofparticular use are selective ADAM-10 inhibitors, those that are “MMP-1sparing.”

All patents, applications, and publications recited herein are herebyincorporated by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention provides compounds useful for inhibiting theADAM-10 protein. Such compounds are useful in the in vitro study of therole of ADAM-10 (and its inhibition) in biological processes. Thepresent invention also comprises pharmaceutical compositions comprisingone or more ADAM-10 inhibitors according to the invention in combinationwith a pharmaceutically acceptable carrier. Such compositions are usefulfor the treatment of cancer, arthritis, and diseases related toangiogenesis, such as renal diseases, heart diseases such as heartfailure, atherosclerosis, and stroke, inflammation, ulcer, infertility,scleroderma, endometriosis, mesothelioma, and diabetes. Correspondingly,the invention also comprises methods of treating forms of cancer,arthritis, and diseases related to angiogenesis in which ADAM-10 plays acritical role. In particular, the invention comprises inhibitorsselective for ADAM-10, relative to MMP-1.

The foregoing merely summarizes certain aspects of the invention and isnot intended to be limiting.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises inhibitors of ADAM-10. In oneembodiment, the invention comprises a compound of structural formula I:

and pharmaceutically acceptable salts, esters, amides, and prodrugsthereof wherein

-   L¹ is —C(O)—, —S(O)₂—, or —(CH₂)_(n)—;-   R¹ is —H, —OR¹¹, —(CH₂)_(n)R¹¹, —C(O)R¹¹, or —NR¹²R¹³;    -   R¹¹, R¹², and R¹³ independently are        -   a) R⁵⁰;        -   b) saturated or mono- or poly-unsaturated C₅-C₁₄-mono- or            fused poly-cyclic hydrocarbyl, optionally containing one or            two annular heteroatoms per ring and optionally substituted            with one or two R⁵⁰ substituents;        -   c) C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, or —C(O)H,            each of which is optionally substituted with one, two or            three substituents independently selected from R⁵⁰ and            saturated or mono- or poly-unsaturated C₅-C₁₄-mono- or fused            poly-cyclic hydrocarbyl, optionally containing one or two            annular heteroatoms per ring and optionally substituted with            one, two or three R⁵⁰ substituents;        -   or R¹² and R¹³ together with the N to which they are            covalently bound, a C₅-C₆ heterocycle optionally containing            a second annular heteroatom and optionally substituted with            one or two R⁵⁰ substituents;-   R² is —R²¹-L²-R²²;    -   R²¹ is saturated or mono- or poly-unsaturated C₅-C₁₄-mono- or        fused poly-cyclic hydrocarbyl, optionally containing one or two        annular heteroatoms per ring and optionally substituted with        one, two, or three R⁵⁰ substituents;    -   L² is —O—, —C(O)—, —CH₂—, —NH—, —S(O₂)— or a direct bond;    -   R²² is saturated or mono- or poly-unsaturated C₅-C₁₄-mono- or        fused poly-cyclic hydrocarbyl, optionally containing one or two        annular heteroatoms per ring and optionally substituted with        one, two, or three R⁵⁰ substituents; and-   R⁵⁰ is R⁵¹-L³-(CH₂)_(n)—;    -   L³ is —O—, —NH—, —S(O)₀₋₂—, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—,        —NHC(O)—, —C₆H₄—, or a direct bond;    -   R⁵¹ is —H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halo,        —CF₃, —OCF₃, —OH, —NH₂, mono-C₁-C₆alkyl amino, di-C₁-C₆alkyl        amino, —SH, —CO₂H, —CN, —NO₂, —SO₃H, or a saturated or mono- or        poly-unsaturated C₅-C₁₄-mono- or fused poly-cyclic hydrocarbyl,        optionally containing one or two annular heteroatoms per ring        and optionally substituted with one, two, or three substituents;-   wherein n is 0, 1, 2, or 3;    provided that an O or S is not singly bonded to another O or S in a    chain of atoms.

In one example, according to paragraph [0013], L¹ is —C(O)— or —S(O)₂—.

In another example, according to paragraph [0014], L¹ is —C(O)— and R¹is —OR¹¹ or —(CH₂)_(n)R¹¹, —OC₁-C₆alkyl-mono-C₁-C₆alkyl amino,—OC₁-C₆alkyl-di-C₁-C₆alkyl amino, —OC₁-C₆alkyl-N-heterocyclyl,—C₁-C₆alkyl-mono-C₁-C₆alkyl amino, —C₁-C₆alkyl-di-C₁-C₆alkyl amino, or—C₁-C₆alkyl-N-heterocyclyl. In a more specific example, R¹ isC₁-C₆-alkoxy-C₁-C₆-alkoxy; and in a still more specific example R¹ ismethoxyethoxy.

In another example, according to paragraph [0015], L¹ is —S(O)₂—, and R¹is —NR¹²R¹³, —(CH₂)_(n)R¹¹, —C₁-C₆alkyl-mono-C₁-C₆alkyl amino,—C₁-C₆alkyl-di-C₁-C₆alkyl amino, or —C₁-C₆alkyl-N-heterocyclyl.

In another example, according to paragraph [0015] or [0016], L² is —O—.

In another example, according to paragraph [0017], R² is phenoxyphenylwherein each phenyl is optionally substituted with one or two R⁵⁰substituents. In a more specific example, the R⁵⁰ substituents are halo.

In another example, according to paragraph [0018], the saturated ormono- or poly-unsaturated C₅-C₁₄-mono- or fused poly-cyclic hydrocarbylcontaining one or two annular heteroatoms per ring is selected from thegroup consisting of morpholinyl, piperazinyl, homopiperazinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl,isobenzofuranyl, chromenyl, pyrrolyl, imidazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, oxadiazolyl, indolyl, quinolinyl, carbazolyl,acrydinyl, and furazanyl, optionally substituted with one or two R⁵⁰substituents.

In another example, according to paragraph [0018], R¹² and R¹³, togetherwith the N to which they are covalently bound, form a heterocycleselected from the group consisting of morpholinyl, piperazinyl,homopiperazinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, pyrrolyl,imidazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxadiazolyl,indolyl, quinolinyl, carbazolyl, acrydinyl, and furazanyl, optionallysubstituted with one or two R⁵⁰ substituents.

In another example, the compound is according to paragraph [0013],having the absolute stereochemistry of structural formula II:

In another example, the compound is according to paragraph [0013],having the absolute stereochemistry of structural formula III:

In another example, the compound of the invention is according toparagraph [0013], wherein -L¹-R¹ is selected from Table 1;

TABLE 1

wherein each R¹⁴ is independently selected from —H, —(CH₂)₁₋₃CO₂H,alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl;and R² is selected from Table 2;

TABLE 2

In another example the compound is according to paragraph [0013],selected from Table 3:

TABLE 3

In another aspect, the invention comprises compounds according toformula IV,

and pharmaceutically acceptable salts, esters, amides, and prodrugsthereof wherein,

-   -   Z is —C(R¹⁵)═, —C(H)═, or —N═;    -   Ar is aryl or heteroaryl, each optionally substituted;    -   R¹⁵ is fluoro;    -   p is 0, 1, 2, or 3;    -   L¹ is —C(O)—, —S(O)₂—, or —(CH₂)_(n)—;    -   L⁴ is nothing or —O—;    -   R¹ is —H, —OR¹¹, —(CH₂)_(n)R¹¹, —C(O)R¹¹, or —NR¹²R¹³;        -   R¹¹, R¹², and R¹³ independently are            -   d) R⁵⁰;            -   e) saturated or mono- or poly-unsaturated C₅-C₁₄-mono-                or fused poly-cyclic hydrocarbyl, optionally containing                one or two annular heteroatoms per ring and optionally                substituted with one or two R⁵⁰ substituents;            -   f) C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, or —C(O)H,                each of which is optionally substituted with one, two or                three substituents independently selected from R⁵⁰ and                saturated or mono- or poly-unsaturated C₅-C₁₄-mono- or                fused poly-cyclic hydrocarbyl, optionally containing one                or two annular heteroatoms per ring and optionally                substituted with one, two or three R⁵⁰ substituents;            -   or R¹² and R¹³ together with the N to which they are                covalently bound, a C₅-C₆ heterocycle optionally                containing a second annular heteroatom and optionally                substituted with one or two R⁵⁰ substituents; and    -   R⁵⁰ is R⁵¹-L³-(CH₂)_(n)—;        -   L³ is —O—, —NH—, —S(O)₀₋₂—, —C(O)—, —C(O)O—, —C(O)NH—,            —OC(O)—, —NHC(O)—, —C₆H₄—, or a direct bond;        -   R⁵¹ is —H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halo,            —CF₃, —OCF₃, —OH, —NH₂, mono-C₁-C₆alkyl amino, di-C₁-C₆alkyl            amino, —SH, —CO₂H, —CN, —NO₂, —SO₃H, or a saturated or mono-            or poly-unsaturated C₅-C₁₄-mono- or fused poly-cyclic            hydrocarbyl, optionally containing one or two annular            heteroatoms per ring and optionally substituted with one,            two, or three substituents;    -   wherein n is 0, 1, 2, or 3;    -   provided that an O or S is not singly bonded to another O or S        in a chain of atoms.

In one example the compound is according to paragraph [0025], wherein-L¹-R¹ is selected from Table 4,

TABLE 4

wherein each R¹⁴ is independently selected from —H, —(CH₂)₁₋₃CO₂H,alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl.

In another example the compound is according to paragraph [0026],wherein Z is —C(R¹⁵)═ or —C(H)═; L⁴ is —O—; and p is at least one.

In another example the compound is according to paragraph [0027],wherein Ar is selected from the group consisting of phenyl, biphenyl,napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl,furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl,benzimidazolyl, and isoxazolyl, each optionally substituted.

In another example the compound is according to paragraph [0028],wherein Ar is phenyl, optionally substituted, with at least one halogen.

In another example the compound is according to paragraph [0029],wherein p is at least two.

In another example the compound is according to paragraph [0030],wherein -L¹-R¹ is —C(═O)OR¹⁴ or —(CH₂)₂OR¹⁴.

In another example the compound is according to paragraph [0031], havingthe structure:

In another example the compound is according to paragraph [0026],wherein Z is —N═; and L⁴ is —O—.

In another example the compound is according to paragraph [0033],wherein Ar is selected from the group consisting of phenyl, biphenyl,napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl,furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl,benzimidazolyl, and isoxazolyl, each optionally substituted.

In another example the compound is according to paragraph [0034],wherein Ar is optionally substituted tetrahydronaphthalene.

In another example the compound is according to paragraph [0035],wherein -L¹-R¹ is —C(═O)OR¹⁴ or —(CH₂)₂₋₃OR¹⁴.

In another example the compound is according to paragraph [0036],wherein p is zero.

In another example the compound is according to paragraph [0037], havingthe structure:

In another example the compound is according to paragraph [0026],wherein Z is —N═; and L⁴ is nothing.

In another example the compound is according to paragraph [0039],wherein Ar is selected from the group consisting of phenyl, biphenyl,napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl,furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl,benzimidazolyl, and isoxazolyl, each optionally substituted.

In another example the compound is according to paragraph [0040],wherein p is zero.

In another example the compound is according to paragraph [0041],wherein Ar is optionally substituted phenyl.

In another example the compound is according to paragraph [0042],wherein -L¹-R¹ is —C(═O)OR¹⁴ or —(CH₂)₂₋₃OR¹⁴.

In another example the compound is according to paragraph [0043], havingthe structure:

In another example the compound is according to paragraph [0026], offormula V,

In another example the compound is according to paragraph [0045],wherein Ar is selected from the group consisting of phenyl, biphenyl,napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl,furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl,benzimidazolyl, and isoxazolyl, each optionally substituted.

In another example the compound is according to paragraph [0046],wherein Ar is phenyl, optionally substituted, with at least one halogen.

In another example the compound is according to paragraph [0046],wherein Ar is selected from,

In another example the compound is according to paragraph [0047],wherein the absolute stereochemistry is according to formula VI,

In another example the compound is according to paragraph [0049],wherein -L¹-R¹ is —C(═O)OR¹⁴ or —(CH₂)₂₋₃OR¹⁴.

In another example the compound is according to paragraph [0050], havingthe structure:

In another example, the invention comprises a pharmaceutical compositioncomprising a compound as described in any of paragraphs [0013]-[0051]and a pharmaceutically acceptable carrier.

In another example, the invention comprises a method of making abis-aryl ether sulfonyl halide according to formula VII:

wherein X is a halide; and W¹ and W² are each independently anoptionally substituted aryl, the method comprising: (a) combining ametal-aryloxide salt of a corresponding hydroxide-substituted arylcompound with a fluoro-substituted nitro aryl compound to make abis-aryl ether nitro-aromatic compound; (b) reducing a nitro group ofthe bis-aryl ether nitro-aromatic compound to produce a correspondinganiline derivative; and (c) converting the corresponding anilinederivative to the bis-aryl ether sulfonyl halide.

In one example, the method is according to paragraph [0053], wherein themetal-aryloxide salt is combined with the fluoro-substituted nitro arylin an organic solvent.

In another example, the method is according to paragraph [0054], whereinthe organic solvent comprises at least one of DMF and acetonitrile.

In another example, the method is according to paragraph [0055], whereinthe metal-aryloxide salt comprises at least one of a cesium salt and apotassium salt.

In another example, the method is according to paragraph [0056], whereinthe corresponding aniline derivative is converted to the bis-aryl ethersulfonyl halide via a diazonium intermediate of said correspondinganiline derivative.

In another example, the method is according to paragraph [0057], whereinthe fluoro-substituted nitro aryl compound is3,4,5-trifluornitrobenzene.

In another example, the method is according to paragraph [0058], whereinthe metal-aryloxide salt is a cesium salt.

In another example, the method is according to paragraph [0059], whereinthe corresponding hydroxide-substituted aryl compound is 4-chlorophenol.

In another example, the method is according to paragraph [0060], whereinthe bis-aryl ether sulfonyl halide is4-(4-chlorophenoxy)-3,5-difluorophenylsulfonyl chloride.

In another aspect, the invention comprises a sulfonyl halide accordingto formula VIII:

wherein X is halogen; R¹⁶, R¹⁷, R¹⁸, and R¹⁹, are each independentlyeither —H or —F; and Ar is aryl or heteroaryl, each optionallysubstituted.

In another example, the sulfonyl halide is according to paragraph[0062], wherein R¹⁶ and R¹⁸ are each —H; and R¹⁷ and R¹⁹ are each —F.

In another example the sulfonyl halide is according to paragraph [0063],wherein Ar is selected from the group consisting of phenyl, biphenyl,napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl,furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl,benzimidazolyl, and isoxazolyl, each optionally substituted.

In another example the sulfonyl halide is according to paragraph [0064],wherein Ar is phenyl, optionally substituted, with at least one halogen.

In another example the sulfonyl halide is according to paragraph [0065],of formula IX:

In another example, the sulfonyl halide is according to paragraph[0066], wherein X is —Cl.

Yet another example of the invention is a method of treating cancer,arthritis, and diseases related to angiogenesis comprising administeringto a mammal in need of such treatment a therapeutically effective amountof a pharmaceutical composition according to paragraph [0052].

Still yet another example of the invention is a method of modulating theactivity of Adam-10 comprising administering to a mammal in need of suchtreatment a therapeutically effective amount of a pharmaceuticalcomposition according to paragraph [0052].

Definitions

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds of the invention and are intended toapply uniformly throughout the specification and claims unless expresslystated otherwise.

The term alkyl refers inclusively to a univalent C₁ to C₂₀ (unlessexplicitly stated otherwise) saturated straight, branched, cyclic, andcombinations thereof alkane moiety and specifically includes methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl,isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl. In certain instances, specificcycloalkyls are defined (e.g. C₃-C₈ cycloalkyl) to differentiate themfrom generically described alkyls (that, again, are intended to construeinclusion of cycloalkyls). Thus “alkyl” includes, e.g., C₃-C₈cycloalkyl. The term “alkyl” also includes, e.g., C₃-C₈ cycloalkyl C₁-C₆alkyl, which is a C₁-C₆ alkyl having a C₃-C₈ cycloalkyl terminus.Alkyl's can be optionally substituted with any appropriate group,including but not limited to one or more moieties selected from halo,hydroxyl, amino, arylalkyl, heteroarylalkyl, alkylamino, arylamino,alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, or phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art or as taught, forexample, in Greene, et al., “Protective Groups in Organic Synthesis,”John Wiley and Sons, Second Edition, 1991.

The term alkoxy refers to the group —O— (substituted alkyl), thesubstitution on the alkyl group generally containing more than onlycarbon (as defined by alkoxy). One exemplary substituted alkoxy group is“polyalkoxy” or —O— (optionally substituted alkylene)-(optionallysubstituted alkoxy), and includes groups such as —OCH₂CH₂OCH₃, andglycol ethers such as polyethyleneglycol and —O(CH₂CH₂O)_(x)CH₃, where xis an integer of between about 2 and about 20, in another example,between about 2 and about 10, and in a further example between about 2and about 5. Another exemplary substituted alkoxy group is hydroxyalkoxyor —OCH₂(CH₂)_(y)OH, where y is for example an integer of between about1 and about 10, in another example y is an integer of between about 1and about 4.

The term alkenyl refers to a univalent C₂-C₆ straight, branched, or inthe case of C₅₋₈, cyclic hydrocarbon with at least one double bond.

The term aryl refers to a univalent phenyl, biphenyl, napthyl, and thelike. The aryl group can be optionally substituted with any suitablegroup, including but not limited to one or more moieties selected fromhalo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in Greene, et al.,“Protective Groups in Organic Synthesis,” John Wiley and Sons, SecondEdition, 1991). As well, substitution on an aryl can include fused ringssuch as in tetrahydronaphthalene, chromen-2-one, dibenzofuran, and thelike. In such cases, e.g. tetrahydronaphthalene, the aryl portion of thetetrahydronaphthalene is attached to the portion of a molecule describedas having an aryl group.

The term heteroatom means O, S, P, or N.

The term heterocycle refers to a cyclic alkyl, alkenyl, or aryl moietyas defined above wherein one or more ring carbon atoms is replaced witha heteroatom.

The term heteroaryl specifically refers to an aryl that includes atleast one of sulfur, oxygen, and nitrogen in the aromatic ring.Non-limiting examples are pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl,pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl,pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl,pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.

The term halo refers to chloro, fluoro, iodo, or bromo.

As used herein, the term pharmaceutically acceptable salts or complexesrefers to salts or complexes that retain the desired biological activityof the above-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to acid addition salts formed with inorganic acids (for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,and polygalacturonic acid. The compounds can also be administered aspharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenyl-acetate).

The term pharmaceutically active derivative refers to any compound thatupon administration to the recipient, is capable of providing directlyor indirectly, the compounds disclosed herein.

In some examples, as will be appreciated by those skilled in the art,two adjacent carbon containing groups on an aromatic system may be fusedtogether to form a ring structure. The fused ring structure may containheteroatoms and may be substituted with one or more substitution groups“R”. It should additionally be noted that for cycloalkyl (i.e. saturatedring structures), each positional carbon may contain two substitutiongroups, e.g. R and R′.

Some of the compounds of the invention may have imino, amino, oxo orhydroxy substituents off aromatic heterocyclic ring systems. Forpurposes of this disclosure, it is understood that such imino, amino,oxo or hydroxy substituents may exist in their corresponding tautomericform, i.e., amino, imino, hydroxy or oxo, respectively.

Compounds of the invention are generally named using ACD/Name (availablefrom Advanced Chemistry Development, Inc. of Toronto, Canada). Thissoftware derives names from chemical structures according to systematicapplication of the nomenclature rules agreed upon by the InternationalUnion of Pure and Applied Chemistry (IUPAC), International Union ofBiochemistry and Molecular Biology (IUBMB), and the Chemical AbstractsService (CAS).

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquaternized nitrogen atoms in their structure.

The compounds of the invention and their pharmaceutically acceptablesalts may exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. The compounds may also exist as geometricisomers. All such single stereoisomers, racemates and mixtures thereof,and geometric isomers are intended to be within the scope of thisinvention.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. When desired, theR- and S-isomers may be resolved by methods known to one skilled in theart, for example by: formation of diastereoisomeric salts or complexeswhich may be separated, for example, by crystallization; via formationof diastereoisomeric derivatives which may be separated, for example, bycrystallization, gas-liquid or liquid chromatography; selective reactionof one enantiomer with an enantiomer-specific reagent, for exampleenzymatic oxidation or reduction, followed by separation of the modifiedand unmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, for example on a chiral support, such as silica witha bound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. It will be understood by one skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns that are sterically impractical and/or syntheticallynonfeasible. “Optionally substituted” refers to all subsequent modifiersin a term, for example in the term “optionally substitutedC₁₋₈alkylaryl,” optional substitution may occur on both the “C₁₋₈alkyl”portion and the “aryl” portion of the molecule; and for example,optionally substituted alkyl includes optionally substituted cycloalkylgroups, which in turn are defined as including optionally substitutedalkyl groups, potentially ad infinitum.

“Substituted” alkyl, aryl, and heterocyclyl, for example, referrespectively to alkyl, aryl, and heterocyclyl, wherein one or more (forexample up to about 5, in another example, up to about 3) hydrogen atomsare replaced by a substituent independently selected from, but notlimited to: optionally substituted alkyl (e.g., fluoroalkyl), optionallysubstituted alkoxy, alkylenedioxy (e.g. methylenedioxy), optionallysubstituted amino (e.g., alkylamino and dialkylamino), optionallysubstituted amidino, optionally substituted aryl (e.g., phenyl),optionally substituted arylalkyl (e.g., benzyl), optionally substitutedaryloxy (e.g., phenoxy), optionally substituted arylalkyloxy (e.g.,benzyloxy), carboxy (—COOH), carboalkoxy (i.e., acyloxy or —OOCR),carboxyalkyl (i.e., esters or —COOR), carboxamido, aminocarbonyl,benzyloxycarbonylamino (CBZ-amino), cyano, carbonyl, halogen, hydroxy,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclyl, nitro, sulfanyl, sulfinyl, sulfonyl, and thio.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about 1 and about 6 carbons)wherein the alkyl group is a straight or branched chain. Acceptableesters also include cycloalkyl esters and arylalkyl esters such as, butnot limited to benzyl. Examples of pharmaceutically acceptable amides ofthe compounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about 1 and about 6 carbons). Amides and esters of the compoundsof the present invention may be prepared according to conventionalmethods. A thorough discussion of prodrugs is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; e.g., biotransformation to a more polar molecule such as byoxidation, reduction, or hydrolysis, or to a conjugate (see Goodman andGilman, “The Pharmacological Basis of Therapeutics” 8.sup.th Ed.,Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be synthesized suchthat the biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as bacterialdigestion, metabolism, enzymatic conversion, and the like.

Experimental Section

The compounds of the invention can be made in accordance with thefollowing general description and following the teachings provided inthe Example Section, below, and methods routine to those of ordinaryskill in the art. The examples are merely illustrative and are notintended to be limiting.

N-Hydroxy-1,4-disubstituted piperazine-2-carboxamides of the presentinvention can be synthesized using the methods described below. Method Abegins with the reaction of piperazine-2-(R)-carboxylic aciddihydrochloride (1), for example, with di-tert-butyl dicarbonate toyield the bis-Boc protected intermediate 2, which is esterified, forexample, with methyl iodide in the presence of cesium carbonate to formmethyl ester 3. The Boc groups are then removed from 3 to yieldpiperazine dihydrochloride intermediate 4.

In one pot, the N4 nitrogen of 4 is selectively acylated, carbamylated,sulfonylated, alkylated, and the like, followed by sulfonylation of theN1 nitrogen to form the disubstituted piperazine 5. The methyl estergroup of 5 is then converted to the hydroxamate in a mixture of DMF and50% aqueous hydroxylamine, for example, to give the correspondingN-hydroxy-1,4-disubstituted piperazine-2-(R)-carboxamide 6, inaccordance with formula I.

Method B begins with the sulfonylation of the N1 nitrogen of mono-Bocprotected piperazine-2-(R)-carboxylic acid 7, for example, through theuse of trimethylsilyl chloride and an appropriate sulfonyl chloride (seesynthesis below) to form intermediate 8. Intermediate 8 is thenesterifed with TMS-diazomethane to form methyl ester 9, followed bydeprotection of the Boc group with TFA to form the TFA salt of 10.Alternatively, compound 8 can be simultaneously esterified andBoc-deprotected using HCl in methanol to form the HCl salt of 10. The N4nitrogen of 10 is acylated, carbamylated, sulfonylated, alkylated, etc.to form methyl ester 5, which is converted to the hydroxamate 6 (seestructure in Method A description) using a mixture of DMF and 50%aqueous hydroxylamine as described above or, alternatively, by treatmentwith hydroxylamine under basic conditions (KOH in MeOH).

Method C begins with the one pot synthesis of the disubstitutedpiperazine-2-(R)-carboxylic acid 8 from the dihydrochloride 1. First,under Schotten-Baumann conditions, the N4 nitrogen of 1 is selectivelyBoc-protected, followed by the addition of triethylamine and theappropriate sulfonyl chloride to sulfonylate the N1 nitrogen to form 8.From intermediate 8, the desired hydroxamates 6 are formed as describedin Method B.

EXAMPLE SECTION Example 1N-Hydroxy-1-[4-(4-fluorophenoxy)-phenyl)]sulfonyl-4-(4-morpholinyl-carbonyl)piperazine-2-(R)-carboxamide(Method A)

Step 1—Formation of1,4-di-tert-butoxycarbonylpiperazine-2-(R)-carboxylic acid.Piperazine-2-(R)-carboxylic acid dihydrochloride (16.6 g, 82 mmol) anddioxane (120 ml) were combined and cooled in an icebath. 5N NaOH (60 ml,300 mmol) was added, followed by (Boc)₂O (41.8 g, 191 mmol). Thereaction mixture was allowed to warm to room temperature with stirringover several hours, then concentrated in vacuo. The resulting aqueousmixture was washed with Et₂O (3×), cooled in an icebath, acidified to pH2-3 with concentrated HCl and extracted with EtOAc (3×). Combined EtOAcextractions were washed with water (1×), saturated NaCl (1×), dried(Na₂SO₄), and concentrated in vacuo to give1,4-di-tert-butoxycarbonylpiperazine-2-(R)-carboxylic acid as a whitesolid (27.0 g, 100%). LC/MS Calcd for [M−H]⁻ 329.2, found 329.2.

Step 2—Formation of methyl 1,4-di-tert-butoxycarbonylpiperazine-2-(R)-carboxylate1,4-Di-tertbutoxycarbonylpiperazine-2-(R)-carboxylic acid (70 g, 212mmol) was dissolved in acetonitrile (1.3 L). Cs₂CO₃ (110 g, 340 mmol)was added and the mixture stirred for 30 minutes at room temperaturebefore the addition of methyl iodide (28 ml, 450 mmol). The reactionmixture was stirred at room temperature overnight, solids were filteredand the filtrate concentrated in vacuo. The resulting oil was dissolvedin EtOAc and any insoluble material filtered. The filtrate wasconcentrated in vacuo to give methyl1,4-di-tert-butoxycarbonylpiperazine-2-(R)-carboxylate (69 g, 95%).LC/MS Calcd for [M+H]⁺ 345.2, found 145.1 (-Boc X 2).

Step 3—Formation of methyl piperazine-2-(R)-carboxylate dihydrochloride.Methyl 1,4-di-tert-butoxycarbonylpiperazine-2-(R)-carboxylate (2.9 g,8.5 mmol) was dissolved in 4M HCl in dioxane (30 ml) and stirred at roomtemperature for 30-60 minutes, forming a thick white precipitate. Thereaction mixture was concentrated in vacuo and the resulting white soliddried under high vacuum to give methyl piperazine-2-(R)-carboxylatedihydrochloride (1.9 g, 100%). LC/MS Calcd for [M+H]⁺ 145.1, found145.1.

Step 4—Formation of methyl1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)pipera-zine-2-(R)-carboxylateMethyl piperazine-2-(R)-carboxylate dihydrochloride (676 mgs, 3.1 mmol)was dissolved in CH₂Cl₂ (7 mls) and DIEA (2.1 mls, 12.4 mmol) and cooledin an icebath. Morpholinecarbonyl chloride (450 mgs, 3.0 mmol) dissolvedin methylene chloride (2.5 mls) was added dropwise with stirring. Afteraddition was complete, the reaction mixture was allowed to warm to roomtemperature and stirred for an additional 2-3 hrs. Additional DIEA (0.6mls, 3.4 mmol) was added, followed by 4-(4-fluorophenoxy)phenylsulfonylchloride (904 mg, 3.1 mmol) and the reaction mixture stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuoand the resulting residue redissolved in EtOAc and washed with water(1×), 1.0N HCl (2×), dried (Na₂SO₄), concentrated in vacuo and purifiedby flash chromatography (3:1 EtOAc:hexanes) to give methyl1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxylate(1.11 g, 70%). LC/MS Calcd for [M+H]⁺ 508.1, found 508.1.

Step 5—Formation ofN-hydroxy-1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carbox-amideMethyl1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxylate(1.11 g, 2.2 mmol) was dissolved in DMF (17 mls) to which was added 50%aqueous NH₂OH (20 mls) and the reaction mixture stirred at roomtemperature overnight. The reaction mixture was poured into cold 1.0NHCl (100-120 mls) and extracted with EtOAc (4×). The combined EtOAcextractions were washed with 10% aqueous LiCl (4×), saturated NaCl (1×),dried (Na₂SO₄), and concentrated in vacuo. The crude product waspurified by flash chromatography (EtOAc) and the resulting pure oil wasdissolved in 1:1 acetonitrile:water and lyophilized to giveN-hydroxy-1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxamideas a white solid (659 mg, 59%). LC/MS Calcd for [M+H]⁺ 509.1, found509.1. ¹HNMR (400 MHz, CD₃OD): δ 7.69 (d, 2H, J=9.2 Hz), 7.04 (m, 4H),6.95 (d, 2H, J=9.2 Hz), 4.30 (m, 1H), 3.76 (m, 1H), 3.50 (m, 7H), 3.10(m, 4H), 2.90 (dd, 1H, J=13.2, 4.4 Hz), 2.72 (m, 1H).

Example 2N-Hydroxy-1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl-4-(ethoxycarbonyl)piperazine-2-(R)-carboxamide(Method B)

Step 1—Formation of1-[4-(4-fluorophenoxy)-3,5-difluoro-phenyl)]sulfonyl-4-boc-piperazine-2-(R)-carboxylicacid 4-Boc-piperazine-2-(R)-carboxylic acid (933 mg, 4.05 mmol), CH₂Cl₂(12 ml), DMF (6 ml), and DIEA (2.5 ml, 14.3 mmol) were combined underN₂. TMS-Cl (810 μl, 6.38 mmol) was added slowly and the mixture stirredat room temperature for approximately 2 hrs.4-4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl chloride (1.43 g, 4.43mmol) dissolved in a minimum of CH₂Cl₂ was added and the mixture stirredat room temperature for another 2 hrs. The reaction mixture was dilutedwith EtOAc and washed with 0.5N HCl (3×), sat'd NaCl (1×), dried(Na₂SO₄), and concentrated in vacuo. The resulting crude oil waspurified by flash chromatography (6:4 hexanes:EtOAc+1% AcOH) to give thedesired product (1.37 g, 65%). LC/MS Calcd for [M+H]⁺ 517.1, found 417.0(-Boc).

Step 2—Formation of methyl1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl-4-boc-piperazine-2-(R)-carboxylate.1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl-4-boc-piperazine-2-(R)-carboxylicacid (1.37 g, 2.65 mmol) was dissolved in CH₂Cl₂ (40 ml) and MeOH (10ml). A mixture of 2M TMS-CHN₂ in hexanes (2.5 ml, 5 mmol) and CH₂Cl₂ (10ml) was added dropwise with stirring and the reaction followed by TLC.Upon completion of the reaction, AcOH (1.0 ml) was added dropwise withstirring. The reaction mixture was further diluted with CH₂Cl₂ andwashed with water (1×), saturated NaHCO₃ (2×), saturated NaCl (1×),dried (MgSO₄), and concentrated in vacuo. The crude oil was purified byflash chromatography (3:1 hexanes:EtOAc) to give the desired product(1.10 g, 78%). LC/MS Calcd for [M+H]⁺ 531.1, found 431.0 (-Boc).

Step 3—Formation of methyl1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl-piperazine-2-(R)-carboxylateTFA salt. Methyl1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl-4-boc-piperazine-2-(R)-carboxylate(1.10 g, 2.07 mmol) was dissolved in a minimum of CH₂Cl₂ to which wasadded neat TFA (10 ml). The mixture was stirred at room temperature forapproximately 30 min, concentrated in vacuo, further dried for severalhours under high vacuum and used without further purification. LC/MSCalcd for [M+H]⁺ 431.1, found 431.0.

Step 4—Formation of methyl1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl-4-(ethoxycarbonyl)piperazine-2-(R)-carboxylate.To a mixture of methyl1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl-piperazine-2-(R)-carboxylateTFA salt (344 mg, 0.63 mmol), CH₂Cl₂ (10 ml), and DIEA (250 μl, 1.43mmol) under N₂ was added ethyl chloroformate (65 μl, 0.68 mmol). Themixture was stirred under N₂ at room temperature for 1.5 hrs, thenwashed with 1.0N HCl (2×), saturated NaCl (1×), dried (Na₂SO₄), andconcentrated in vacuo. The crude residue was purified by flashchromatography (3:1 hexanes:EtOAc) to give the desired product (218 mgs,69%). LC/MS Calcd for [M+H]⁺ 503.1, found 503.0.

Step 5—Formation ofN-hydroxy-1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]sulfonyl-4-(ethoxycarbonyl)piperazine-2-(R)-carboxamide.A 1.7M solution of NH₂OH in MeOH was prepared by mixing a solution ofKOH (2.80 g, 50.0 mmol) in MeOH (7.0 ml) with a hot solution of NH₂OHHCl salt (2.40 g, 34.5 mmol) in MeOH (12.0 ml) and filtering theresulting solids after cooling to room temperature. Methyl1-[4-(4-fluorophenoxy)-3,5-difluorophenyl)]-sulfonyl-4-(ethoxycarbonyl)piperazine-2-(R)-carboxylate(218 mg, 0.43 mmol) was dissloved in the 1.7M NH₂OH in MeOH solution(4.0 ml) and stirred at room temperature for 30-45 minutes. The reactionmixture was then diluted with 1.0N HCl and extracted with EtOAc (3×).Combined EtOAc extractions were washed with saturated NaCl (1×), dried(Na₂SO₄), and concentrated in vacuo. The resulting crude residue waspurified by flash chromatography (1:1 EtOAc:hexanes) to give a colorlessfilm which was lyophilized from 1:1 AcCN:H₂O to give the desired productas a white solid (136 mg, 62%). LC/MS Calcd for [M+H]⁺ 504.1, found504.0. ¹HNMR (400 MHz, CD₃OD): δ 7.58 (m, 2H), 7.03 (m, 4H), 4.27 (m,2H), 4.07 (m, 3H), 3.75 (m, 2H), 3.30 (m, 1H), 3.06 (m, 1H), 1.22 (m,3H).

Example 3N-Hydroxy-1-[4-(4-cyanophenoxy)-3-fluorophenyl)]sulfonyl-4-(2-methoxy-1-ethoxycarbonyl)piperazine-2-(R)-carboxamide(Method C)

Step 1—Formation of1-[4-(4-cyanophenoxy)-3-fluorophenyl)]sulfonyl-4-boc-piperazine-2-(R)-carboxylicacid.

Piperazine-2-(R)-carboxylic acid dihydrochloride (1.25 g, 6.1 mmol),dioxane (15 mls) and water (6.0 mls) were combined and cooled in anicebath. 9N NaOH (2.0 mls, 18 mmol) was added slowly with stirring,followed by (Boc)₂O (1.35 g, 6.2 mmol). The reaction mixture was allowedto warm to room temperature and stirred for an additional 3-4 hrs. Et₃N(1.8 mls, 13 mmol) was added, followed by4-cyanophenoxy-3-fluorophenylsulfonyl chloride (2.00 g, 6.4 mmol). Thereaction mixture is stirred at room temperature for 1-2 hrs, thenconcentrated in vacuo. The resulting residue was partitioned between1.0N HCl and EtOAc. Phases were separated and the aqueous phase wasfurther extracted with EtOAc (2×). Combined EtOAc extractions werewashed with 1.0N HCl (1×), saturated NaCl (1×), dried (MgSO₄), andconcentrated in vacuo. The resulting residue is purified by flashchromatography (7:3 hexanes:EtOAc+1% AcOH) to give the desired product(1.1 g, 35%). LC/MS Calcd for [M−H]⁻ 504.1, found 504.3.

Step 2. Methyl1-[4-(4-cyanophenoxy)-3-fluorophenyl)]sulfonyl-4-boc-piperazine-2-(R)-carboxylatewas made in the same manner as Example 2, step 2, except purification byflash chrmoatography was unnecessary. 1.10 g recovered (97%). LC/MSCalcd for [M+H]⁺ 520.1, found 420.1 (-Boc).

Step 3. Methyl1-[4-(4-cyanophenoxy)-3-fluorophenyl)]sulfonyl-piperazine-2-(R)-carboxylateTFA salt was made in the same manner as Example 2, step 3. LC/MS Calcdfor [M+H]⁺ 420.1, found 420.2.

Step 4. Methyl1-[4-(4-cyanophenoxy)-3-fluorophenyl)]sulfonyl-4-(2-methoxy-1-ethoxycarbonyl)piperazine-2-(R)-carboxylatewas made in the same manner as Example 2, step 4. 438 mgs recovered(83%). LC/MS Calcd for [M+H]⁺ 522.1, found 522.2.

Step 5.N-Hydroxy-1-[4-(4-cyanophenoxy)-3-fluorophenyl)]sulfonyl-4-(2-methoxy-1-ethoxycarbonyl)piperazine-2-(R)-carboxamidewas made in the same manner as Example 2, step 5. 46 mg recovered (10%).LC/MS Calcd for [M−H]⁻ 521.1, found 521.2. ¹HNMR (400 MHz, CD₃OD): δ7.73 (m, 3H), 7.65 (m, 1H), 7.34 (m, 1H), 7.19 (d, 2H, J=8.4 Hz), 4.29(m, 2H), 4.14 (m, 3H), 3.74 (m, 2H), 3.55 (m, 2H), 3.33 (s, 3H), 3.25(m, 1H), 3.04 (m, 1H).

Example 4 Synthesis of Sulfonyl Chloride Intermediates Example 4a4-(4-fluorophenoxy)-3,5-difluorophenylsulfonyl chloride

Step 1. A mixture of 3,4,5-trifluoronitrobenzene (20.0 g, 113 mmol,commercially available from AsymChem of Durham, N.C.), dry DMF (100 ml),4-fluorophenol (13.9 g, 124 mmol), and CS₂CO₃ (56 g, 172 mmol) wasstirred under N₂ at 60-70° C. for 1-2 hrs. After cooling to roomtemperature, the reaction mixture was partitioned between H₂O and EtOAc.The phases were separated and the aqueous phase was further extractedwith EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×),dried over Na₂SO₄, and concentrated in vacuo to give4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (32.0 g, 105%) which wasused in the next step without further purification. ¹H NMR (DMSO-d₆): δ7.15 (m, 2H), 7.22 (m, 2H), 8.31 (d, 2H, J=7.6 Hz).

Step 2. A mixture of 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (30.4g, 113 mmol), EtOAc (300 ml), 10% Pd/C (2.6 g) was stirred under anatmosphere of H₂ at room temperature and pressure for approximately 6hrs. The reaction mixture was filtered through Celite and concentratedin vacuo to give 4-(4-fluorophenoxy)-3,5-difluoroaniline (26.5 g, 98%)which was used in the next step without further purification. ¹H NMR(CDCl₃): δ 3.82 (s, 2H), 6.26 (d, 2H, J=8.4 Hz), 6.88 (m, 2H), 6.93 (m,2H).

Step 3. A solution of NaNO₂ (8.4 g, 122 mmol) in H₂O (20 ml) was addeddropwise to a mixture of 4-(4-fluorophenoxy)-3,5-difluoroaniline (26.5g, 111 mmol), AcOH (160 ml), and conc. HCl (160 ml) cooled in anice/NaCl/H₂O bath. After addition was complete, the mixture was stirredan additional 20-30 minutes before a mixture of SO₂ (74 g, 1.15 mol) inAcOH (140 ml) and CuCl₂-2H₂O (11.1 g, 65 mmol) in H₂O (16 ml) was added.The reaction mixture was removed from the ice bath and stirred at roomtemperature for 1-2 hrs. The reaction mixture was poured into ice waterand extracted with CH₂Cl₂ (3×). The combined CH₂Cl₂ extractions werewashed with sat'd NaCl (1×), dried over Na₂SO₄, and concentrated invacuo. The resulting crude oil was purified by flash chromatography (9:1hexanes:EtOAC) to give 4-(4-fluorophenoxy)-3,5-difluorophenyl sulfonylchloride (29.8 g, 83%). ¹H NMR (CDCl₃): δ 6.94 (m, 2H), 7.10 (m, 2H),7.71 (d, 2H, J=6.4 Hz).

Example 4b 4-(4-Chlorophenoxy)-3,5-difluorophenylsulfonyl chloride

Step 1. A mixture of 3,4,5-trifluoronitrobenzene (6.6 g, 37 mmol), dryDMF (30 ml), 4-chlorophenol (5.26 g, 41 mmol), and Cs₂CO₃ (18.8 g, 58mmol) was stirred under N₂ at 60-70 C for 1-2 hrs. After cooling to roomtemperature, the reaction mixture was partitioned between H₂O and EtOAc.The phases were separated and the aqueous phase was further extractedwith EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×),dried over Na₂SO₄, and concentrated in vacuo to give4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (11.3 g, 106%) which wasused in the next step without further purification. ¹H NMR (CDCl₃): δ6.90 (d, 2H, J=7.6 Hz), 7.28 (d, 2H, J=7.6 Hz), 7.94 (d, 2H, J=6.4 Hz).Note: K₂CO₃/acetonitrile can be used in lieu of Cs₂CO₃/DMF.

Step 2. A mixture of 4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (10.6g, 37 mmol), toluene (150 ml), H₂O (150 ml), iron powder (6.9 g, 124mmol), and ammonium acetate (9.3 g, 120 mmol) was heated to reflux withstirring for 2-3 hrs. After cooling to room temperature, the reactionmixture was filtered through Celite with thorough washing with H₂O andEtOAc. The filtrate was transferred to a separatory funnel and thephases separated. The aqueous phase was further extracted with EtOAc(2×). The combined organic phases were washed with H₂O (1×), sat'd NaCl(1×), dried over Na₂SO₄, and concentrated in vacuo to give4-(4-chlorophenoxy)-3,5-difluoroaniline (10.8 g, 113%) which was used inthe next step without further purification. ¹H NMR (CDCl₃): δ 3.81 (s,2H), 6.27 (d, 2H, J=9.2 Hz), 6.85 (d, 2H, J=9.2 Hz), 7.21 (d, 2H, J=9.2Hz).

Step 3. A solution of NaNO₂ (2.8 g, 41 mmol) in H₂O (7.0 ml) was addeddropwise to a mixture of 4-(4-chlorophenoxy)-3,5-difluoroaniline (9.5 g,37 mmol), AcOH (50 ml), and conc. HCl (50 ml) cooled in an ice/NaCl/H₂Obath. After addition was complete, the mixture was stirred an additional20-30 minutes before a mixture of SO₂ (25 g, 290 mmol) in AcOH (50 ml)and CuCl₂-2H₂O (3.8 g, 22 mmol) in H₂O (6.0 ml) was added. The reactionmixture was removed from the ice bath and stirred at room temperaturefor 1-2 hrs. The reaction mixture was poured into ice water andextracted with CH₂Cl₂ (3×). The combined CH₂Cl₂ extractions were washedwith sat'd NaCl (1×), dried over Na₂SO₄, and concentrated in vacuo. Theresulting crude oil was purified by flash chromatography (9:1hexanes:EtOAC) to give 4-(4-chlorophenoxy)-3,5-difluorophenylsulfonylchloride (11.0 g, 87%). ¹H NMR (CDCl₃): δ 6.92 (d, 2H, J=7.2 Hz), 7.30(d, 2H, J=7.2 Hz), 7.72 (d, 2H, J=4.8 Hz).

Example 4c 3,4,5-trifluorobenzenesulfonyl chloride

To a 2000 mL round-bottomed flask was added 800 mL distilled H₂O and astir bar. Upon stirring, the flask was cooled to −10° C. in anice-acetone bath. The flask was fitted with a 500 mL addition funnel andSOCl₂ (300 mL, 4.1 mol, 10 eq.) was added dropwise over a period of 1 h.After complete addition, the solution was stirred for 4 h while warmingto room temperature.

Meanwhile, in a separate 500 mL recovery flask was added3,4,5-trifluoroaniline (61 g, 0.41 mol, 1.0 eq.), conc. HCl (150 mL),and a stir bar. The resulting suspension was stirred vigorously andcooled to −10° C. The flask was fitted with a 250 mL addition funnel anda solution of NaNO₂ (34.3 g, 0.50 mol, 1.2 eq.) in H₂O (125 mL) wasadded to the suspension dropwise over a period of 10 min. The reactionmixture, now nearly homogeneous, is yellow-orange in color. The reactionmixture was stirred for an additional 30 min while carefully maintainingthe temperature at −10° C.

The flask containing the SOCl₂/H₂O solution is cooled again to −10° C.and a catalytic amount of Cu(I)Cl (˜50 mg) was added. The solution turnsdark green in color. The flask was fitted with a 500 mL addition funnel(previously chilled to 0° C.) and the 3,4,5-trifluorodiazobenzenesolution was quickly transferred to the funnel. The solution wasimmediately added dropwise over a period of 3 min. After addition, thereaction mixture slowly turns darker green in color, but after stirringfor 5 min becomes bright, lime green. The reaction was stirred for anadditional hour while warming to room temperature. The reaction mixturewas transferred to a separatory funnel and extracted with CH₂Cl₂ (3×200mL). The organic phases are combined and dried over anhydrous Na₂SO₄,filtered, and concentrated to give a dark-bronze oil (79.5 g, 83%).

Example 5 Enzyme Assays

mADAM-10 or hADAM-10 activity was measured as the ability to cleave a10-residue peptide(DABCYL-Leu-Leu-Ala-Gln-Lys-*-LeuArg-Ser-Ser-Arg-EDANS). This peptidewas based on the TNF-α cleavage site (Leu⁶²-Arg⁷¹); however, we foundthat replacement of Ala⁷⁶-Val⁷⁷ with Lys-Leu resulted in a peptide witha 5-fold greater affinity for ADAM-10 than the native TNF-α peptide.Enzyme was diluted to a final active concentration of 5 nM in Buffer A(50 mM HEPES 8.0, 100 mM NaCl, 1 mM CaCl2 and 0.01% NP-40). Serialdilutions for compounds were performed ranging from 100 μM to 0.5 nMusing a Beckman Biomek 2000 in polypropylene plates (Greiner). 20 μl ofenzyme solution was added to 10 μl of compound in buffer A, and allowedto incubate for 15 min in 384 well black, Greiner, microtiter plates(#781076). 20 μl of substrate (12.5 μM in Buffer A) was then added,resulting in final reaction conditions of 2 nM ADAM-10, 5 μM substrate,and compound concentrations ranging from 20 uM to 0.1 nM. The reactionwas incubated for 2 hr at RT, and fluorescence was measured at Ex355,Em460 on a Wallac Victor 2 fluorescence reader. For final analysis ofpotent inhibitors, a similar reaction was set up with a final activeADAM-10 concentration of 0.1 nM. This reaction was incubated for 16 hrat RT and fluorescence was read using identical conditions.

One aspect of the invention is, for example, piperazine-derivedhydroximates according to formula I, which are selective ADAM-10inhibitors. In one embodiment, such inhibitors comprise a bis-aryl ethersubstitution for —R² (—R²¹-L²-R²², where R²¹ is phenylene, L² is oxygen,and R²² is phenyl), the proximal ring (R²¹) of which is substitutedparticularly with one or more halogens, more particularly with one ormore flourines, even more particularly with two or more flourines. Forexample, by combining such groups with appropriate substitution, -L¹-R¹and —R²², inhibitors that are selective for ADAM-10 are produced.

Table 5 below shows structure activity relationship data for selectedcompounds of the invention when tested in vitro with variousmetalloproteases. Inhibition is indicated as IC₅₀ with the followingkey: A=IC₅₀ less than 50 nM, B=IC₅₀ greater than 50 nM, but less than1000 nM, C=IC₅₀ greater than 1000 nM, but less than 20,000 nM, andD=IC₅₀ greater than 20,000 nM. Blank cells indicate lack of data only.The abbreviations in Table 5 are defined as follows: TACE stands forTNF-alpha converting enzyme (also known as ADAM-17; MMP-1 stands forFibroblast collagenase; MMP-2 stands for 72 kDa gelatinase (gelatinaseA); MMP-3 stands for Stromelysin-1; MMP-8 stands for Neutrophilcollagenase; MMP-9 stands for 92 kDa gelatinase (gelatinase B); andMMP-13 stands for collagenase-3.

TABLE 5 ADAM- MMP- 10 TACE MMP-1 MMP-2 MMP-3 MMP-8 MMP-9 13 ENTRYSTRUCTURE IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ 1

A A A A A 2

A A A A A 3

A B A C A 4

A B A A A 5

A B A B A 6

A B A A A 7

A B A A A 8

A B A A A 9

A C A C C 10

A C A C A 11

B D B C D 12

A C A B A 13

A C A B A 14

B D A D A 15

A B C A B A A A 16

A D A C A 17

A C A B A 18

A D A B A 19

A D A B A 20

A D A C A 21

A D A C B 22

A C A B A 23

A D A C A 24

A D A C A 25

A D A B A 26

A D A C A 27

A C A B A 28

A B A B A 29

A C A B A 30

A B C A B A B A 31

A B C A B A 32

A C A B A 33

A C A B A 34

A A C A B A 35

A C A B A 36

A C A B A 37

A B C A A A 38

A B C A A A 39

A B A A A 40

A C A B A 41

A C A A A 42

A C A C A 43

A D A B A 44

A D A C B 45

A B C A B A 46

A C A B A 47

A D A B A 48

A D A B A 49

C D A B A 50

C D D B A 51

B C B C B 52

A C A C A 53

A B A B A 54

A A B A A A 55

A C A B A 56

A C A B A 57

B D B C B 58

A B A B A 59

A B C A B A 60

B D A C A 61

B D C D C 62

B D A C A 63

B D B C B 64

A B A A A 65

B A A A A 66

A B A A A

Table 6 contains physical characterization data for selected compoundsof the invention. ¹H-NMR data were taken with a Varian AS400Spectrometer (400 MHz, available from Varian GmbH, Darmstadt, Germany).The entry numbers in Table 6 correspond to those of Table 5 (and theircorresponding structures).

TABLE 6 Entry ¹H NMR Data (or MS data) 1 (CD3OD): 7.68(d, 2H),7.18-7.14(m, 4H), 7.05(d, 2H), 4.32(m 1H), 4.23(d, 1H), 4.15(m, 2H),4.00(d, 1H), 3.68-3.64(m, 2H), 3.55(m, 2H), 3.35(s, 3H), 3.2(m, 1H),3.00(m, 1H) ppm. 2 (CD3OD): 7.69(d, 2H, J=9.2Hz), 7.04(m, 4H), 6.95(d,2H, J=9.2Hz), 4.30(m, 1H), 3.76(m, 1H), 3.50(m, 7H), 3.10(m, 4H),2.90(dd, 1H, J=13.2, 4.4Hz), 2.72(m, 1H) ppm. 3 (CD3OD): 7.68(dd, 1H),7.55(dd, 1H), 7.15-7.10(m, 4H), 7.04(dd, 1H), 4.28-4.12(m, 2H),4.15-4.00(m, 3H), 3.70-3.65(m, 2H), 3.55-3.50(m, 2H), 3.33(s, 3H),3.22(m, 1H), 3.03(m, 1H) ppm. 4 (CD3OD): 7.68(dd, 1H), 7.57(dd, 1H),7.38(d, 2H), 7.13(t, 1H), 7.08(d, 1H), 4.28-4.12(m, 2H), 4.15-4.00(m,3H), 3.70-3.65(m, 2H), 3.55-3.50(m, 2H), 3.33(s, 3H), 3.22(m, 1H),3.03(m, 1H) ppm. 5 (CD3OD): 7.75-7.71(m, 3H), 7.65(dd, 1H), 7.33(dd,1H), 7.20(d, 2H), 4.32-4.26(m, 2H), 4.16-4.05(m, 3H), 3.81-3.75(m, 2H),3.56(m, 2H), 3.34(s, 3H), 3.27(m, 1H), 3.06(m, 1H) ppm. 6 (CDCl3):7.73(d, 1H), 7.61(d, 1H), 7.34(d, 2H, J=8.8Hz), 6.99(d, 2H, J=8.8Hz),6.98(m, 1H), 4.67(s, 1H), 4.23(d, 1H), 3.64(m, 5H), 3.44(d, 1H), 3.35(m,2H), 3.21(m, 2H), 3.10(m, 4H) ppm. 7 (CD3OD): 7.68-7.64(m, 3H), 7.58(d,1H), 7.22(t, 1H), 7.08(d, 2H), 4.30(m, 1H), 3.78(d, 1H), 3.75-3.48(m,7H), 3.08-3.00(m, 5H), 2.81(m, 1H) ppm. 8 (CD3OD): 7.75(d, 1H), 7.60(d,1H), 7.18-7.14(m, 4H), 7.07(t, 1H), 4.4(m, 1H), 3.86(d, 1H),3.78-3.55(m, 7H), 3.24-3.14(m, 4H), 3.08(dd, 1H), 2.87(m, 1H) ppm. 9(CD3OD): 7.60-7.58(m, 2H), 7.08-7.00(m, 4H), 4.3-4.2(m, 2H),4.08-4.02(m, 1H), 3.75-3.70(m, 2H), 3.23-3.18(m, 1H), 3.12-2.90(m, 1H)ppm 10 (CD3OD): 7.49(d, 2H), 7.08-7.00(m, 4H), 4.3-4.2(m, 2H),4.18-4.05(m, 3H), 3.75-3.70(m, 2H), 3.55-3.50(m, 2H), 3.33(s, 3H),3.33-3.25(m, 1H), 3.15-3.00(m, 1H) ppm. 11 (CD3OD): 7.65(d, 2H),7.08-6.98(m, 4H), 4.58(d, 1H), 4.05(dd, 1H), 3.81(ddd, 1H), 3.63(d, 1H),3.46(d, 1H), 3.35(dd, 1H), 3.18(ddd, 1H) ppm. 12 (CD3OD): 7.62(m, 2H),7.08-7.00(m, 4H), 4.40(s, 1H), 3.86(d, 1H), 3.80-3.74(m, 2H),3.65-3.58(m, 5H), 3.25-3.12(m, 5H), 2.96(m, 1H) ppm. 13 (CD3OD):7.60-7.58(m, 2H), 7.08-7.00(m, 4H), 4.3-4.2(m, 2H), 4.08-4.02(m, 3H),3.75-3.70(m, 2H), 3.27(m, 1H), 3.05(m, 1H) ppm. 14 (CD3OD): 7.65-7.62(m,2H), 7.08-7.00(m, 4H), 4.45(s, 1H), 3.80(d, 1H), 3.52(t, 1H), 3.10(d,1H), 2.72(d, 1H), 2.21(s, 3), 2.16(d, 1H), 1.96(t, 1H) ppm. 15 (CD3OD):7.60(d, 2H), 7.32(d, 2H), 7.03(d, 2H), 4.32-4.26(m, 2H), 4.16-4.05(m,3H), 3.81-3.75(m, 2H), 3.56(m, 2H), 3.34(s, 3H), 3.27(m, 1H), 3.06(m,1H) ppm. 16 MS: Calculated for C23H26ClF2N5O6S: 573.13; Found:574.72(M+1). 17 (CD3OD): 7.60(d, 2H, J=7.2Hz), 7.32(d, 2H, J=8.8Hz),6.98(d, 2H, J=9.2Hz), 4.21(m, 2H), 4.08(m, 1H), 3.80-3.60(m, 5H),3.40(m, 1H), 3.23(m, 2H), 3.04(m, 3H), 2.21(m, 1H), 2.50-1.50(m, 4H)ppm. 18 (CD3OD): 7.51(d, 2H, J=7.6Hz), 7.23(d, 2H, J=6.4Hz), 6.88(d, 2H,J=6.4Hz), 4.19-4.11(m, 2H), 3.98-3.94(m, 1H), 3.73-3.67(m, 4H), 3.59(m,1H), 3.50-3.14(m, 5H), 3.03-2.91(m, 3H), 1.99-1.88(m, 4H) ppm. 19(CD3OD): 7.82(br. s, 1H), 7.69(d, 2H), 7.38(d, 2H), 7.05(d, 2H), 4.58(brs, 1H), 3.88(m, 1H), 3.60(td, 1H), 3.19-2.91(m, 4H), 2.85-2.70(m, 6H),2.40-2.29(m, 2H) ppm. 20 (CD3OD): 7.71(d, 2H), 7.35(d, 2H), 7.00(d, 2H),4.58(br s, 1H), 3.80(m, 1H), 3.40-3.33(m, 2H), 3.30-3.20(m, 2H), 3.05(s,3H), 2.96(s, 3H), 2.81(m, 1H), 2.40-2.30(m, 2H) ppm. 21 DMSO-d₆: 9.8(br,1H), 9.0(br, 1H), 7.85(m, 2H), 7.4(m, 2H), 7.1(m, 2H), 4.4(m, 3H),3.6(m, 7H), 3.0(m, 3H), 2.0(m, 4H). 22 (CD3OD): 7.61(m, 2H), 7.32(d, 2H,J=8.8Hz), 6.99(d, 2H, J=8.8Hz), 4.40-4.20(m, 4H), 4.10(m, 1H),3.80-3.60(m, 4H), 3.50(m, 1H), 3.40-3.15(m, 4H), 2.89(d, 3H),2.15-2.00(m, 2H) ppm. 23 DMSO-d₆: 10.2(br, 1H), 9.0(br, 1H), 7.8(m, 2H),7.4(m, 2H), 7.1(m, 2H), 4.4(m, 4H), 4.0(m, 7H), 3.3(m, 8H), 1.2(t, 3H).24 DMSO-d₆: 7.8(m, 2H), 7.4(m, 2H), 7.1(m, 2H), 3.8(m, 11H), 3.4(m, 2H),3.0(m, 4H), 2.8(3, 3H). 25 DMSO-d₆: 10.2(br, 1H), 9.0(br, 1H), 7.8(m,2H), 7.45(m, 2H), 7.2(m, 2H), 4.4(m, 4H), 3.8(m, 7H), 3.4(m, 6H). 26DMSO-d₆: 9.4(br, 1H), 9.0(br, 1H), 7.8(m, 2H), 7.4(m, 2H), 7.1(m, 2H),4.85(m, 1H), 4.1(m, 2H), 3.0(m, 6H), 3.4(m, 4H), 3.0(m, 2H), 1.9(m, 4H).27 (CD3OD): 7.54(d, 2H, J=7.2Hz), 7.25(d, 2H, J=8.8Hz), 6.89(d, 2H,J=8.8Hz), 4.15(m, 3H), 3.90(m, 1H), 3.78(m, 1H), 3.60(m, 2H),3.40-3.20(m, 4H), 3.05(m, 1H), 3.00(m, 1H), 2.80(m, 1H), 2.70(m, 1H),1.80-1.60(m, 4H), 1.40(m, 1H) ppm. 28 (CDCl3): 9.20(br s, 1H), 7.58(d,2H), 7.30(d, 2H), 6.90(d, 2H), 4.65(br s, 1H), 4.19(d, 1H), 3.95-3.60(m,2H), 3.33(m, 1H), 3.15-2.80(m, 2H), 2.88(s, 3H) ppm. 29 (CDCl3): 7.61(d,2H), 7.29(d, 2H), 6.90(d, 2H), 4.71(br s, 1H), 3.75(br d, 1H),3.60-3.48(m, 2H), 3.42(s, 3H), 3.20(d, 1H), 3.09(td, 1H), 2.88(br d,1H), 2.75(m, 1H), 2.60-2.49(m, 3H) ppm. 30 (CDCl3): 11.8(br. S, 1H),7.61(d, 2H), 7.55(br. s, 1H), 7.26(d, 2H), 6.90(d, 2H), 4.71(s, 1H),4.28(d, 1H), 3.70-3.62(m, 4H), 3.48(d, 1H), 3.36-3.16(m, 5H), 3.00(t,1H) ppm. 31 (CDCl3): 11.23(br s, 1H), 7.59(d, 2H), 7.26(d, 2H), 6.95(d,2H), 4.70(br s, 1H), 3.40(br d, 1H), 4.23(d, 1H), 3.85-3.38(m, 10H),3.20-2.90(m, 2H) ppm. 32 (CDCl3): 7.46(d, 2H, J=6.8Hz), 7.26(m, 4H),6.91(d, 2H, J=9.2Hz), 4.60(s, 1H), 4.00(m, 1H), 3.80(m, 2H), 3.60(m,2H), 3.40(m, 1H), 2.60(m, 2H) ppm. 33 (CDCl3): 7.54(d, 2H, J=5.6Hz),7.25(d, 2H, J=9.2Hz), 6.86(d, 2H, J=9.2Hz), 4.60(m, 1H), 4.40(m, 2H),4.05(m, 1H), 3.75(m, 2H), 3.45(m, 1H), 3.0(m, 1H), 2.93(s, 2H) ppm. 34(CD3OD): 8.61(br. s, 1H), 7.75(m, 2H), 7.67(d, 2H), 7.33(d, 2H), 7.03(d,2H), 4.54(m, 1H), 4.03-3.88(m, 3H), 3.60(m, 2H), 3.12(m, 1H), 2.93(m,1H) ppm. 35 (CDCl3): 7.63(d, 1H), 7.49(d, 1H), 7.28(m, 2H), 6.90(dd,2H), 4.51(m, 1H), 4.42(m, 1H), 4.14(br d, 1H), 3.82-2.91(m, 8H),1.84-1.45(m, 6H) ppm. 36 (CDCl3): 7.54(d, 2H, J=6.4Hz), 7.30(d, 2H,J=8.8Hz), 6.91(d, 2H, J=8.8Hz), 4.70(m, 1H), 4.10(m, 1H), 3.90(m, 1H),3.60(m, 1H), 3.40(m, 1H), 2.83(s, 6H), 2.80(m, 2H) ppm. 37 (CD3OD):7.65(d, 2H), 7.31(d, 2H), 7.00(d, 2H), 4.60(m, 1H), 4.00(m, 2H), 3.69(m,2H), 3.40-3.00(m, 5H), 2.82(m, 1H), 1.70-1.40(m, 6H) ppm. 38 (CD3OD):7.69(d, 2H), 7.33(d, 2H), 7.00(d, 2H), 4.60(br s, 1H), 3.92(br t, 2H),3.62-3.41(m, 10H), 2.90(dd, 1H), 2.70(td, 1H) ppm. 39 (CD3OD): 7.65(d,2H), 7.33(d, 2H), 7.00(d, 2H), 4.59(br s, 1H), 3.88(m, 2H), 3.70-3.15(m,5H), 2.90-2.45(m, 6H) ppm. 40 (CD3OD): 7.48(d, 2H), 7.22(dd, 2H),6.99(t, 1H), 6.89(d, 2H), 4.23-4.15(m, 2H), 4.05-3.95(m, 3H),3.67-3.64(m, 2H), 3.45(m, 2H), 3.25(s, 3H), 3.2(m, 1H), 3.00(m, 1H) ppm.41 (CDCl3): 7.46(d, 2H, J=6.8Hz), 7.26(m, 4H), 6.91(d, 2H, J=9.2Hz),4.60(s, 1H), 4.00(m, 1H), 3.80(m, 2H), 3.60(m, 2H), 3.40(m, 1H), 2.60(m,2H) ppm. 42 (CD3OD): 8.79(br. s, 2H), 7.70(m, 4H), 7.38(d, 2H), 7.00(d,2H), 4.40(m, 2H), 4.00-3.00(m, 5H) ppm. 43 (CDCl3): 7.50(d, 2H), 7.23(m,2H), 6.87(d, 2H), 4.86(d, 1H), 4.57(d, 1H), 4.05(m, 2H), 3.38(m, 2H),3.04(m, 1H), 2.31(t, 2H), 1.53(s, 2H), 1.25(s, 6H), 0.85(t, 3H) ppm. 44(CDCl3): 7.52(d, 2H, J=6.4Hz), 7.24(d, 2H, J=8.8Hz), 6.87(d, 2H,J=8.4Hz), 4.97(d, 1H), 4.71(s, 1H), 4.05(d, 1H), 3.80(d, 1H), 3.37(m,1H), 3.26(t, 1H), 3.05(d, 1H), 2.62(m, 1H), 1.54(m, 2H), 1.80(m, 2H),1.18(m, 4H), 0.85(dt, 6H) ppm. 45 (CDCl3): 8.15(s, 1H), 7.65(s, 1H),7.47(m, 2H), 7.21(d, 2H, J=8.8Hz), 6.84(d, 2H, J=8.4Hz), 6.43(s, 1H),4.63(s, 1H), 3.60(m, 3H), 2.80(m, 3H) ppm. 46 MS: Calculated forC24H26ClF2N5O8S: 617.12; Found: LC/MS: 618.2(M+1). 47 (CD3OD): 8.60(m,2H), 8.25(d, 1H), 7.83(m, 1H), 7.62-7.50(m, 2H), 7.22(m, 2H), 6.85(m,2H), 4.60-4.20(m, 2H), 4.15-3.95(m, 2H), 3.85-3.65(m, 2H), 3.50-3.40(m,2H), 3.10(m, 1H) ppm. 48 (CD3OD): 9.60(br s, 1H), 8.60(m, 4H), 7.95(t,1H), 7.60(d, 2H), 7.37(d, 2H), 7.00(d, 2H), 4.60(br s, 1H), 4.15(br d,1H), 3.93(br d, 1H), 3.71-3.42(m, 2H), 2.80-2.50(m, 2H) ppm. 49 (CD3OD):8.50(d, 1H), 7.99(d, 1H), 7.79(d, 1H), 7.58(m, 2H), 7.40(m, 4H), 7.11(m,3H), 4.60(br s, 1H), 4.20(br d, 1H), 3.85(br d, 1H), 3.49(m, 2H),3.09(s, 6H), 2.50(dd, 1H), 2.30(td, 1H) ppm. 50 (CD3OD): 8.09(s, 1H),7.80(dd, 2H), 7.60-7.42(m, 3H), 7.31(m, 3H), 7.95(m, 3H), 4.60(br s,1H), 4.08(m, 1H), 3.91(br d, 1H), 3.60(m, 2H), 3.10(s, 6H), 2.42(dd,1H), 2.22(td, 1H) ppm. 51 (CDCl3): 7.63(d, 2H, J=7.6Hz), 7.56(d, 2H,7.2Hz), 7.53-7.37(m, 6H), 7.24(m, 3H), 6.86(d, 2H, J=8.8Hz), 3.90(s,1H), 3.70(m, 2H), 3.45(m, 1H), 3.30(m, 3H) ppm. 52 (CD3OD): 8.45(br s,2H), 7.78(d, 1H), 7.58(m, 3H), 7.38(m, 2H), 7.00(m, 2H), 4.80-4.05(m,2H), 4.00-3.77(m, 5H), 3.45-3.05(m, 2H) ppm. 53 (CD3OD): 7.70(d, 2H),7.39(d, 2H), 7.00(d, 2H), 4.60(br s, 1H), 4.00(m, 2H), 3.79(m, 2H),4.60-3.40(m, 6H), 3.20-2.90(m, 4H), 2.00-1.40(m, 6H) ppm. 54 (CD3OD):7.70(d, 2H), 7.39(d, 2H), 7.00(d, 2H), 4.60(br s, 1H), 4.00(m, 2H),3.75(m, 2H), 4.49(m, 4H), 3.18(m, 2H), 2.93(s, 6H) ppm. 55 (CD3OD):7.66(d, 2H), 7.35(d, 2H), 7.03(d, 2H), 4.58(m, 1H), 4.03-3.92(m, 3H),3.71-3.68(m, 3H), 3.27-3.25(t, 2H), 3.15-3.13(m, 4H), 2.97-2.93(m, 1H),2.88(s, 3H), 2.86-2.82(m, 5H) ppm 56 (CD3OD): 7.68-7.66(d, 2H),7.35-7.33(d, 2H), 7.04-7.01(d, 2H), 4.57(m, 1H), 4.13-4.08(q, 2H),4.02-3.98(m, 1H), 3.71-3.68(m, 2H), 3.46(m, 4H), 3.26-3.23(t, 2H),3.19-3.15(dd, 1H), 2.96-2.95(m, 1H), 2.77-2.73(m, 2H), 2.46(m, 4H),1.26-1.22(t, 3H) ppm 57 (CD3OD): 7.19(d, 2H), 7.14(d, 2H), 6.83(d, 2H),4.48(br s, 1H), 3.95-3.92(br d, 1H), 3.83-3.80(br d, 1H), 3.58-3.53(m,6H), 3.15(dd, 2H), 2.94(dd, 1H), 2.75-2.74(td, 1H), 2.63-2.60(t, 2H),2.40-2.39(m, 4H) ppm 58 (CD3OD): 9.00(d, 1H), 8.23(d, 1H), 8.07(d, 1H),7.92-7.86(m, 2H), 7.52(m, 1H), 7.22(m, 1H), 4.50(m, 1H), 3.90-3.57(m,8H), 3.22-3.08(m, 5H), 2.97(m, 1H) ppm. 59 (CD3OD): 8.54(d, 2H), 7.77(brs, 1H), 7.57-7.50(m, 2H), 7.44-7.42(m, 1H), 7.27-7.22(m, 2H),6.95-6.92(m, 2H), 4.40-4.20(m, 1H), 3.85-3.60(m, 3H), 3.57-3.18(m, 2H),3.10-2.95(m, 1H) ppm 60 MS: calculate for C29H27ClF2N4O7S2: 680.10;found: 681.20(M+1). 61 MS: calculated for C24H20Cl3F2N3O7S2: 668.98;found: 669.90(M+1). 62 (CD3OD): 7.63(d, 2H, J=7.2Hz), 7.25(d, 2H,J=9.2Hz), 6.93(d, 2H, J=9.2Hz), 5.79(m, 1H), 5.47(s, 1H), 5.44(d, 1H),4.56(d, 1H), 4.00(d, 1H), 3.70-3.50(m, 4H), 3.35(d, 1H), 2.99(d, 1H),2.88(t, 1H) ppm. 63 (CD3OD): 7.66(d, 2H, J=7.6Hz), 7.35(d, 2H, J=8.8Hz),6.99(d, 2H, J=9.2Hz), 3.85(d, 1H), 3.67(s, 2H), 3.61(d, 1H), 3.44(m,2H), 3.04(d, 1H), 2.83(dd, 1H), 2.66(dt, 1H) ppm. 64 (CD3OD): 8.45(d,1H), 8.10(dd, 1H), 7.12(d, 1H), 7.02(d, 1H), 6.86-6.82(m, 2H),4.33-4.25(m, 2H), 4.15-4.05(m, 3H), 3.70-3.65(m, 2H), 3.55(m, 2H),3.35(s, 3H), 3.25(m, 1H), 3.05(m, 1H), 2.78(m, 4H), 1.80(m, 4H) ppm. 65(CD3OD): 8.47(d, 1H), 8.12(dd, 1H), 7.22-7.09(m, 5H), 4.33-4.25(m, 2H),4.15-4.05(m, 3H), 3.70-3.65(m, 2H), 3.55(m, 2H), 3.33(s, 3H), 3.25(m,1H), 3.05(m, 1H) ppm. 66 (CD3OD): 9.96(d, 1H), 8.20(d, 1H), 8.14(d, 1H),7.90(d, 1H), 7.86(d, 1H), 7.50(m, 1H), 7.21(m, 1H), 4.40(m, 1H), 4.28(d,1H), 4.12-4.05(m, 3H), 3.75-3.70(m, 2H), 3.52(m, 2H), 3.30(s, 3H),3.25(m, 1H), 3.06(m, 1H) ppm.

1. A compound of structural formula I:

and pharmaceutically acceptable salts thereof wherein -L¹-R¹ is selectedfrom:

and

wherein each R¹⁴ is independently selected from —H, —(CH₂)₁₋₃CO₂H,alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; and R² is selected from:

and


2. A compound of structural formula I:

and pharmaceutically acceptable salts thereof wherein L¹ is —C(O)—,—S(O)₂—, or —(CH₂)_(n)—; R¹ is C₁-C₆-alkoxy-C₁-C₆-alkoxy; R² is—R²¹-L²-R²²; R²¹ is saturated or mono- or poly-unsaturated C₅-C₁₄-mono-or fused poly-cyclic ring, optionally containing one or two annularheteroatoms per ring and optionally substituted with one, two, or threeR⁵⁰ substituents; L² is —O—, —C(O)—, —CH₂—, —NH—, —S(O₂)— or a directbond; R²² is saturated or mono- or poly-unsaturated C₅-C₁₄-mono- orfused poly-cyclic ring, optionally containing one or two annularheteroatoms per ring and optionally substituted with one, two, or threeR⁵⁰ substituents; and R⁵⁰ is R⁵¹-L³-(CH₂)_(n)—; L³ is —O—, —NH—,—S(O)₀₋₂—, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C₆H₄—, or adirect bond; R⁵¹ is —H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halo,—CF₃, —OCF₃, —OH, —NH₂, mono-C₁-C₆alkyl amino, di-C₁-C₆alkyl amino, —SH,—CO₂H, —CN, —NO₂, —SO₃H, or a saturated or mono- or poly-unsaturatedC₅-C₁₄-mono- or fused poly-cyclic ring, optionally containing one or twoannular heteroatoms per ring and optionally substituted with one, two,or three substituents; wherein n is 0, 1, 2, or 3; provided that an O orS is not singly bonded to another O or S.
 3. The compound according toclaim 2, wherein R¹ is methoxyethoxy.
 4. The compound according to claim2, wherein L² is —O—.
 5. The compound according to claim 4, wherein, R²is phenoxyphenyl wherein each phenyl is optionally substituted with oneor two R⁵⁰ substituents.
 6. The compound according to claim 5, whereinthe saturated or mono- or poly-unsaturated C₅-C₁₄-mono- or fusedpoly-cyclic ring containing one or two annular heteroatoms per ring isselected from the group consisting of morpholinyl, piperazinyl,homopiperazinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, furyl,thienyl, pyranyl, isobenzofuranyl, chromenyl, pyrrolyl, imidazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl,carbazolyl, acrydinyl, and furazanyl, optionally substituted with one ortwo R⁵⁰ substituents.
 7. The compound according to claim 1, having theabsolute stereochemistry of structural formula II:


8. The compound according to claim 1, having the absolutestereochemistry of structural formula III:


9. A compound selected from:

and

or a pharmaceutically acceptable salt of any of the above compounds. 10.A compound according to formula IV,

and pharmaceutically acceptable salts thereof wherein, Z is —C(R¹⁵)═,—C(H)═, or —N═; Ar is aryl or heteroaryl, each optionally substituted;R¹⁵ is fluoro; p is 1, 2, or 3; L¹ is —C(O)—, —S(O)₂—, or —(CH₂)_(n)—;L⁴ is nothing or —O—; R¹ is —H, —OR¹¹, —(CH₂)_(n)R¹¹, —C(O)R¹¹, or—NR¹²R¹³; R¹¹, R¹², and R¹³ independently are j) R⁵⁰; k) saturated ormono- or poly-unsaturated C₅-C₁₄-mono- or fused poly-cyclic ring,optionally containing one or two annular heteroatoms per ring andoptionally substituted with one or two R⁵⁰ substituents; l) C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, or —C(O)H, each of which is optionallysubstituted with one, two or three substituents independently selectedfrom R⁵⁰ and saturated or mono- or poly-unsaturated C₅-C₁₄-mono- orfused poly-cyclic ring, optionally containing one or two annularheteroatoms per ring and optionally substituted with one, two or threeR⁵⁰ substituents; or R¹² and R¹³ together with the N to which they arecovalently bound, a C₅-C₆ heterocycle optionally containing a secondannular heteroatom and optionally substituted with one or two R⁵⁰substituents; and R⁵⁰ is R⁵¹-L³-(CH₂)_(n)—; L³ is —O—, —NH—, —S(O)₀₋₂—,—C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C₆H₄—, or a direct bond;R⁵¹ is —H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halo, —CF₃, —OCF₃,—OH, —NH₂, mono-C₁-C₆alkyl amino, di-C₁-C₆alkyl amino, —SH, —CO₂H, —CN,—NO₂, —SO₃H, or a saturated or mono- or poly-unsaturated C₅-C₁₄-mono- orfused poly-cyclic ring, optionally containing one or two annularheteroatoms per ring and optionally substituted with one, two, or threesubstituents; wherein n is 0, 1, 2, or 3; provided that an O or S is notsingly bonded to another O or S.
 11. The compound according to claim 10,wherein -L¹-R¹ is selected from:

and

wherein each R¹⁴ is independently selected from —H, —(CH₂)₁₋₃CO₂H,alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl.
 12. The compound according to claim 11, wherein Z is—C(R¹⁵)═ or —C(H)═; L⁴ is —O—; and p is at least one.
 13. The compoundaccording to claim 12, wherein Ar is selected from the group consistingof phenyl, biphenyl, napthyl, tetrahydronaphthalene, chromen-2-one,dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl,thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl,quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,purinyl, carbazolyl, benzimidazolyl, and isoxazolyl, each optionallysubstituted.
 14. The compound according to claim 13, wherein Ar isphenyl, optionally substituted, with at least one halogen.
 15. Thecompound according to claim 14, wherein p is at least two.
 16. Thecompound according to claim 15, wherein -L¹-R¹ is —C(═O)OR¹⁴ or—(CH₂)₂OR¹⁴.
 17. The compound according to claim 9, having thestructure:


18. The compound according to claim 11, wherein Z is —N═; and L⁴ is —O—.19. The compound according to claim 18, wherein Ar is selected from thegroup consisting of phenyl, biphenyl, napthyl, tetrahydronaphthalene,chromen-2-one, dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl,pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl,pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl,pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl,each optionally substituted.
 20. The compound according to claim 19,wherein Ar is optionally substituted tetrahydro-naphthalene.
 21. Thecompound according to claim 20, wherein -L¹-R¹ is —C(═O)OR¹⁴ or—(CH₂)₂₋₃OR¹⁴.
 22. The compound according to claim 9, having thestructure:


23. The compound according to claim 11, wherein Z is —N═; and L⁴ isnothing.
 24. The compound according to claim 23, wherein Ar is selectedfrom the group consisting of phenyl, biphenyl, napthyl,tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl, furyl,pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl,benzimidazolyl, and isoxazolyl, each optionally substituted.
 25. Thecompound according to claim 24, wherein Ar is optionally substitutedphenyl.
 26. The compound according to claim 25, wherein -L¹-R¹ is—C(═O)OR¹⁴ or —(CH₂)₂₋₃OR¹⁴.
 27. The compound according to claim 9,having the structure:


28. The compound according to claim 11, of formula V,


29. The compound according to claim 28, wherein Ar is selected from thegroup consisting of phenyl, biphenyl, napthyl, tetrahydronaphthalene,chromen-2-one, dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl,pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl,pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl,pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl,each optionally substituted.
 30. The compound according to claim 29,wherein Ar is phenyl, optionally substituted, with at least one halogen.31. The compound according to claim 29, wherein Ar is selected from,


32. The compound according to claim 30, wherein the absolutestereochemistry is according to formula VI,


33. The compound according to claim 32, wherein -L¹-R¹ is —C(═O)OR¹⁴ or—(CH₂)₂₋₃OR¹⁴.
 34. A pharmaceutical composition comprising a compound asdescribed in claim 1, and a pharmaceutically acceptable carrier.